GP 130 lacking the transmembrane domain

ABSTRACT

A novel splice-variant of gp 130 is disclosed, together with DNA sequence coding for it, pharmaceutical formulations comprising it, and its use ensuring the correct development of pre-implantation embryos.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT Application No.PCT/GB95/02243, filed Sep. 21, 1995, now abandoned.

FIELD OF THE INVENTION

The present invention relates to a novel human gp130 protein, DNAsequences coding for this protein, its use in therapy, particularly inin vitro fertilisation, as well as pharmaceutical formulationscomprising such a protein.

BACKGROUND OF THE INVENTION

Successful embryo implantation requires correct development of thepre-implantation embryo, resulting in a hatched blastocyst which is ableto implant into receptive endometrium. A considerable body of data hasbeen collected which supports the idea that soluble growth factors, ifsecreted by the uterine epithelium, act directly on the embryo tocontrol this process (Anderson, E. D., J. Cellular Biochem., 53: 280-287(1993) and Schultz, G. A. and Hevner, S., Mutat Res., 296: 17-31 (992)).

In addition, developing embryos have been shown to produce a variety ofcytokines which may act in an autocrine fashion on the endometrium toinfluence its receptivity. Examples of growth factors shown to beproduced by human embryos include IL-1, IL-6, CSF-1 and TNF-α (Zolti etal, Fertil. Steril., 56 (1991) 265-272 and Witkin et al, J. Reprod.Immunol., 19 (1991) 85-93). TNF-α has been shown to be present inculture medium of human embryos up to the morula stage, but not thatfrom the blastocyst (Lachappelle et al, Human Reproduction, 8: 1032-1038(1993)). Production of cytokines by the embryo may therefore beregulated in a stage-specific manner.

Data on the possible direct effects of cytokines on embryos have comeprimarily from experiments in mice where many cytokines have been shownto affect the development of preimplantation embryos in vitro. RFN-γ andCSF-1, at physiological concentrations, inhibit the number of embryosdeveloping to the blastocyst stage (Hill et al, J. Immunol. , 139 (1987)2250-2254). TNF-α has also been shown to have more subtle effects.Although TNF-α has no apparent effect on rates of blastocyst formation,it appears to specifically inhibit proliferation of cells contributingto the inner cell mass (ICM), which results in blastocysts with areduced ICM (Pampfer et al, Endocrinology, 134: 206-212 (1994)).

Other growth factors also have specific effects on ICM cells. Forinstance, insulin-like growth factors 1 and 2 stimulate ICMproliferation, whereas leukaemia inhibitory factor (LIF) inhibits theirdifferentiation (Harvey et al, Mol. Reprod. Dev., 31 (1992) 195-199).

As mentioned above, IL-6 is one of the growth factors which has beenshown to be produced by human embryos. IL-6 is a protein which controlsthe proliferation and differentiation of many cell types in mammals, andin addition has a role in the control of the immune system. Binding ofIL-6 to IL-6R initiates the association of IL-6R with a third componentknown as gp130, which actually transmits the signal through the cellmembrane (Taga et al, PNAS, 89: 10998-11001). gp130 is a transmembraneprotein, i.e. it extends through the membrane and projects into thecytoplasm, thus it has distinct domains. In this way, IL-6 "signal"transmission is mediated by means of this protein.

EP-A-0411946 discloses a recombinant gp130 protein, as well as DNAsequences coding for such a protein and methods for its cloning.

Yasukawa et al, Immunology Letters, 31 (1992) 123-130, discloses asoluble, recombinant form of gp130, produced by removing thetransmembrane and cytoplasmic regions of the membrane bound form of theprotein.

Narazaki et al, Blood., 82, No 4 (1993) 1120-1126, disclosed thatsoluble forms of gp130 exist and may have potential to inhibit signalsnormally mediated by transmembrane gp130.

SUMMARY OF THE INVENTION

The present invention relates to a novel human gp130 protein, DNAsequences coding for this protein, its use in therapy, particularly inin vitro fertilization, as well as pharmaceutical compositionscomprising such a protein.

The invention also relates to an isolated and substantially purifiedgp130 encoded by a DNA sequence.

The invention further relates to the use of gp130 to antagonize theaction of one or more growth factors, wherein the growth factors are oneor more of IL-6, LIF, CNTF, Oncostatin M or IL-II.

The invention also relates to the use of gp130 to ensure the correctdevelopment of pre-implantation embryos.

The invention further relates to a pharmaceutical composition comprisinggp130 together with pharmaceutically acceptable excipients. Theinvention also relates to the use of this pharmaceutical composition forantagonizing the action of one or more growth factors. The inventionfurther relates to the use of this pharmaceutical composition forensuring the correct development of pre-implantation embryos.

The invention also relates to a method for antagonizing the action ofone or more growth factors in a pre-implantation embryo which comprisesthe step of administering to the embryo gp130.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

There has now been found a novel form of gp130, lacking thetransmembrane portion, which form arises by means of alternativesplicing of the sequence coding for the transmembrane gp130. This formof gp130 may bind to complexes of, for example, IL-6 receptor, resultingin a blocking of the association of the complex with transmembranegp130.

The novel splicing pattern, as well as resulting in loss of thetransmembrane domain, also results in a frameshift, leading to 45 newamino acids before an in frame stop codon.

Thus, the present invention provides gp130 which includes the followingC-terminal sequence (SEQ ID NO:1):

    Glu Leu Lys Asn Thr Ser Gly Leu Met Phe Gln Ile Leu                             - Gln Arg Val Ile Leu Pro Ser Gly His Leu Thr Leu Leu                         - Gln Gly Thr Ile Leu Ile Gln Lys Ile Lys Cys Ile Gln                         - Met Ala Ile Ser Leu Met                                               

or a C-terminal sequence which is substantially homologous thereto.

Preferably, the novel gp130 of the invention has the above-notedsequence from amino acid position 614. In one embodiment the novel gp130of the invention has a sequence at positions 1-613 substantiallyhomologous to that shown in FIG. 2 (SEQ ID NO:6).

At the amino acid level, a protein sequence may be regarded assubstantially homologous to another protein sequence if a significantnumber of the constituent amino acids exhibit homology. At least 40%,50%, 60%, 70%, 80%, 90%, 95% or even 99%, in increasing order ofpreference, of the amino acids may be homologous.

Thus, activation of the alternative splicing mechanism can result in theproduction of a novel gp130 in human blastocysts, resulting ininactivation of the effects of, for example, LIF, which in turn mayallow differentiation of the inner cell mass, allowing ICMdifferentiation to proceed. Clearly, therefore, the novel gp130 of theinvention can be used in the treatment of preimplantation embryos toensure correct differentiation and development prior to implantation ina subject.

In addition, the invention also provides a DNA sequence coding for aprotein of the invention which sequence includes a sequencesubstantially homologous to (SEQ ID NO:2):

    GAA TTA AAA AAC ACA TCT GGC CTA ATG TTC CAG ATC CTT                             - CAA AGA GTC ATA TTG CCC AGT GGT CAC CTC ACA CTC CTC                         - CAA GGC ACA ATT TTA ATT CAA AAG ATC AAA TGT ATT CAG                         - ATG GCA ATT TCA CTG ATG TAA                                           

"DNA sequence substantially the same" includes all other nucleic acidsequences which, by virtue of the degeneracy of the genetic code, alsocode for the given amino acid sequence or which are substantiallyhomologous to such a sequence.

Sequences having substantial homology may be regarded as those whichwill hybridise to the nucleic acid sequence shown in FIG. 2 (SEQ IDNO:5) under stringent conditions (for example, at 35 to 65° C. in a saltsolution of about 0.9M)

DNA constructs comprising DNA sequences of the invention form anotheraspect of the present invention.

As discussed herein, the protein of the invention is useful inantagonising the action of certain growth factors, thus enabling certaindevelopment processes to be "switched on" in preimplantation embryos.Thus, in a further aspect, the present invention provides the use of theprotein of the invention in antagonising the action of one or moregrowth factors, including IL-6, Leukaemia Inhibitory Factor (LIF),Oncostatin Myciliary Neurotrophic Factor (CNTF) and IL-II.

In addition, the invention also provides the use of the protein of theinvention in the manufacture of a medicament for use in ensuring correctdevelopment in preimplantation embryos. Preferably, the medicament isused to ensure that differentiation of the ICM commences at the correcttime.

The medicament is preferably presented in the form of a pharmaceuticalformulation comprising the protein of the invention together with one ormore pharmaceutically acceptable carriers and/or excipients. Suchpharmaceutical formulations form a yet further aspect of the presentinvention.

A final aspect of the present invention provides a method forantagonising the action of one or more growth factors which comprisesthe step of treating a pre-implantation embryo with the protein of thepresent invention, preferably in the form of a pharmaceuticalformulation. Preferably the invention provides a method for ensuringcorrect development of a preimplantation embryo.

The invention will now be described by means of the following examples,which examples should not be construed as in any way limiting thepresent invention. The examples refer to the following figures whichshow:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: the sequence of the soluble gp130 (SEQ ID NO:4) and a DNAsequence (SEQ ID NO:3) coding for it;

FIG. 2: the sequence of native gp130 (SEQ ID NO:5 and 6);

FIG. 3: agarose gel showing the products of nested RT-PCR amplificationon RNA from human embryos. Each panel shows the products ofamplification with primers specific for different cDNA targets.Amplified cDNAs from different embryos were loaded in each lane. Lanesare labelled according to cDNA labels in Table 1 (below). Additionalsamples were: lane p, first trimester trophoblast; lane q, cDNA from 200BeWO cells; lane r, 10 ng human genomic DNA; and lane s, no input cDNA,as a negative control. DNA molecular weight markers were a 123 base pairladder loaded in lane i. The sizes of the expected PCR products areshown in bp.

                  TABLE 1                                                         ______________________________________                                        Human embryo cDNAs and controls                                                name stage of development                                                    ______________________________________                                                a   2 cell                                                                         b 3 cell                                                           c 4 cell                                                                      d 6 cell                                                                      e 8 cell                                                                      f monila                                                                      g blastocyst                                                                  h culture supernatant for a to g                                              j three pooled blastocysts                                                    k culture supernatant for j                                                   l 2 × 6 cell and 1 × 8 cell                                       m culture supernatant for l                                                   n 1 × 4 cell and 1 × 6 cell                                       o culture supernatant for n                                                 ______________________________________                                         samples a to h are from the same donor.                                  

FIG. 4: primers used for RT-PCR (SEQ ID NOS:7 through 14).

EXAMPLES Example 1 Embryo Culture and RNA Extraction

Crypopreserved human embryos which had been fertilised as part of an IVFprogram were used in this study. These embryos had been donated forresearch purposes by the parents and this study complied with therequirements of the Human Embryology and Fertilisation Authority, andthe local ethical committee. Frozen embryos were thawed and cultured inEarles balanced salts medium supplemented with 0.4% human serum albumin(Armour Pharmaceuticals UK), until the required developmental stage,then flash frozen in liquid nitrogen in 5 μl of culture fluid (and thuslysed by ice crystals). An identical volume of culture supernatant wasfrozen as a control. Any remaining cumulus cells were removed duringroutine handling.

Total RNA from first trimester trophoblast was isolated by the method ofChomsczynski and Sacchi, Anal. Biochem., 162: 156-159 (1987) in whichfrozen tissue is homogenised in 5 ml of buffer containing 4 Mguanidinium thiocyanate (Gibco BRL Livingston, Scotland), 25 mM sodiumcitrate pH 7.0, 0.5% sarcosyl and 0.1 M 2-mercaptoethanol. The lysatewas acidified by the addition of 0.5 ml of 2 M sodium acetate pH 4, andphenol-chloroform extracted using 5 ml of buffer saturated phenol and 1ml chloroform-isoamylalcohol (49:1 v/v). The suspension was placed onice for 15 minutes and centrifuged at 10,000 g for 20 minutes at 4° C.The aqueous phase containing RNA was precipitated, washed twice in 70%ethanol, dried and resuspended in TE (10 mM Tris-HCl pH 7.4 and 1 mMEDTA). The concentration of RNA was determined spectrophotometrically at260 nm.

RNA was prepared from single human embryos using a scaled down protocolbased on the above procedure. To assist precipitation of the RNA 100 μgof carrier yeast tRNA (Gibco BRL, Livingston, Scotland) was added at thehomogenisation step. The remaining details are as described above,except that all the volumes were 50 fold less and the whole procedurewas carried out in 400 μl Eppendorf tubes.

Example 2 Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)

cDNA was synthesised from half the total RNA from each embryo using AMVreverse transcriptase (Super RT, HT Biotech, Cambridge, UK). 3-5micrograms of RNA was primed with oligo dT (Pharmacia), according to themanufacturers instructions for 60 minutes at 42° C. PCR amplification ofthe cDNA preparations was performed as previously described (Sharkey, A.et al, Molecular Endocrinol., 6: 1235-1241 (1992)) with a HybaidOmnigene DNA thermal cycler in a final volume of 30 μl using 1 U of TaqDNA polymerase (Cetus, Emeryville, Calif.) and 10 μM of each of the pairof external primers (see FIG. 4) in the manufacturer's recommendedbuffer. The following cycle profile was used: 30s at 95° C., 30s at X°C. , 30s at 72° C. for 30 cycles, where X is the annealing temperaturefor each pair of cytokine primers.

    ______________________________________                                                External Primers (° C.)                                                            Internal Primers (° C.)                            ______________________________________                                        gp130     49            54                                                      HistRNA 52 59                                                               ______________________________________                                    

Oligonucleotide primers

Oligonucleotide primers for gp130 and HistidylRNA synthetase weresynthesised on a Cruachem PS250 DNA synthesiser. Primer sequences weredesigned from published nucleotide sequences (see FIG. 4), such thatamplification of any contaminating genomic DNA would result in adifferently sized product from the cDNA species.

Because of the small amount of material, two pairs of primers were usedfor each target cDNA, in a nested PCR protocol. One thirtieth of thecDNA products were amplified using Amplitaq (Cetus), in themanufacturers recommended buffer. Following 30 cycles of PCR using theexternal primer pair, one fiftieth of the first round reaction wastransferred to a fresh tube containing the inner primer pair, andsubjected to a further 30 rounds of amplification. As negative control,an equal volume of the culture fluid in which the embryo was grown wasextracted and subjected to RT-PCR in the same way. Also, 200 cells ofthe BeWo cell line (ECACC No 86082803) were extracted as positivecontrol.

The primers used in this study are shown in FIG. 4, together with thesize of the expected product. The identity of each product was confirmedby cloning and sequencing as described previously (Sharkey et al, Mol.Endocrinol. (1992)). To ensure that the product detected resulted fromamplification of cDNA rather than contaminating genomic DNA, primerswere chosen to cross intron/exon boundaries. Ten nanograms of genomicDNA was also subjected to PCR at the same time as the cDNA to verify noproduct of the expected size resulted from genomic DNA.

RESULTS

The technique of RT-PCR was applied to total RNA extracted from humanembryos produced by in vitro fertilisation. Embryos were cultured to theappropriate stage, then quick-frozen in liquid nitrogen. Stored embryoswere thawed and total RNA extracted. In order to produce detectableRT-PCR product from total RNA extracted from a single embryo, a nestedPCR protocol was employed in which the cDNA was subjected to two sets ofPCR amplification with an external primer pair, followed by an internalpair. Primers were based on published cDNA sequences and designed tospan intron-exon boundaries so that amplification of contaminatinggenomic DNA could be readily distinguished from cDNA products.

Initially, cDNA from each embryo was tested with primers for histidyltRNA synthetase (HistRS) to confirm successful RNA isolation and reversetranscription. The primers used gave rise to weak products of greaterthan 400 bp from genomic DNA and 110 bp from cDNA derived from HistRSMRNA. Transcripts for Hist RS were detected in MRNA from embryos at allstages of development, as well as in decidua and the choriocarcinomacell line BeWo, used as positive controls (FIG. 3, lanes p and qrespectively). No product was detected in an equal volume of embryoculture supernatant extracted and subjected co RT-PCR in the same way,indicating that there was no contamination of the culture withextraneous CDNA or RNA.

Examples of similar RT-PCR analysis with primers for gp130 are shown inFIG. 3. Stocks of cDNA were reverse transcribed from each RNA sample ontwo separate occasions and the PCR assays were repeated twice on eachcDNA stock. The results are shown in FIG. 3, which displays phe patternof expression of gp130 during preimDlantation development. The identityof the PCR fragment of the correct size was confirmed by sequencing ofthe cloned PCR product. In cases where novel sized products were seen,these were also cloned and sequenced.

For gp130, the Predicted fragment is 712 bp. However, during the morulato blastocyst transition, a novel, smaller transcript was detected ofapproximately 600 bp. This result appeared consistent since, in samplej, which derives from cDNA made from 3 pooled blastocysts, both productswere detected simultaneously. Upon cloning and sequencing, the smallerproduct appeared to arise due to an alternative splicing event whichremoves the exon encoding the transmembrane domain. The predictedsequence of the novel transcript is shown in FIG. 1. The novel splicingpattern also involves a frameshift, resulting in 45 new amino acids,before an in frame stop codon.

DISCUSSION

Many growth factors have been shown to influence the development ofcultured preimplantation mammalian embryos (for review see Anderson, E.D., J. Cellular Biochem., 53: 280-287 (1993) and Schultz, G. A. andHevner, S., Mutat Res., 296: 17-31 (1992)).

However, there is good evidence for species to species differences inexpression of growth factor receptors in preimplantation development.For instance, EGF mRNA is expressed in the pig embryo but has not beenfound at any stage in mouse preimDlantation embryos (Vaughan et al,Development, 116: 663-669 (1992); Rapolee et al, Science, 241: 1823-1825(1988); and Watson, A. J. et al, Biol. Reprod., 50: 725-733 (1994)).Therefore the usefulness of these studies to researchers interested infactors controlling human preimplantation development is limited. Inaddition, the specific growth factors and receptors investigated in suchstudies frequently have been chosen on an ad hoc basis. Both for ethicaland practical reasons, such an approach is not suitable for use withhuman embryos. We have therefore used a nested RT-PCR method which hasallowed us to screen for the expression of growth factor and receptormRNAs in single human preimplantation embryos. This method has beenwidely is used over the last few years in other species since it isreliable, sensitive and economical in its use of embryo material.

RT-PCR with primers for Histidyl-tRNA synthetase was used on cDNAsamples to confirm that cDNA had been successfully prepared form eachembryo RNA sample. cDNA specific for this housekeeping gene wassuccessfully detected in cDNA samples made even from a single 2-cellembryo, indicating that the method was sufficiently sensitive for thisstudy.

We found that during the morula to blastocyst transition, the size ofthe gp130 PCR product decreased by about 100 bp. Sequencing of thesmaller product indicated that it results from a novel splice variant ofthe gp130 mRNA. This new splice variant lacks the transmembrane domain,and would be expected to produce a novel form of gp130. Soluble gp130protein has recently been detected in human serum and has been shown toantagonise the action of IL-6 and LIFR. When the cytokines associatewith their respective receptors, soluble gp130 is able to bind to thiscomplex, blocking association with membrane bound gp130. The possibilityis that selective expression of the novel gp130 in the blastocoel cavityin the late blastocyst stage would inactivate the effects of LIF inpreventing differentiation of the linear cell mass, allowing ICMdifferentiation to proceed.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                   - -  - - (1) GENERAL INFORMATION:                                             - -    (iii) NUMBER OF SEQUENCES: 14                                          - -  - - (2) INFORMATION FOR SEQ ID NO:1:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 45 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: Not Relev - #ant                                       - -     (ii) MOLECULE TYPE: peptide                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                               - - Glu Leu Lys Asn Thr Ser Gly Leu Met Phe Gl - #n Ile Leu Gln Arg        Val                                                                             1               5   - #                10  - #                15              - - Ile Leu Pro Ser Gly His Leu Thr Leu Leu Gl - #n Gly Thr Ile Leu Ile                  20      - #            25      - #            30                   - - Gln Lys Ile Lys Cys Ile Gln Met Ala Ile Se - #r Leu Met                          35          - #        40          - #        45                       - -  - - (2) INFORMATION FOR SEQ ID NO:2:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 138 base - #pairs                                                 (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                               - - GAATTAAAAA ACACATCTGG CCTAATGTTC CAGATCCTTC AAAGAGTCAT AT -             #TGCCCAGT     60                                                                 - - GGTCACCTCA CACTCCTCCA AGGCACAATT TTAATTCAAA AGATCAAATG TA -            #TTCAGATG    120                                                                 - - GCAATTTCAC TGATGTAA             - #                  - #                      - # 138                                                                  - -  - - (2) INFORMATION FOR SEQ ID NO:3:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1977 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (ix) FEATURE:                                                                  (A) NAME/KEY: CDS                                                             (B) LOCATION: 1..1974                                                - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                               - - ATG TTG ACG TTG CAG ACT TGG GTA GTG CAA GC - #C TTG TTT ATT TTC CTC           48                                                                       Met Leu Thr Leu Gln Thr Trp Val Val Gln Al - #a Leu Phe Ile Phe Leu             1               5 - #                 10 - #                 15              - - ACC ACT GAA TCT ACA GGT GAA CTT CTA GAT CC - #A TGT GGT TAT ATC AGT           96                                                                       Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pr - #o Cys Gly Tyr Ile Ser                        20     - #             25     - #             30                  - - CCT GAA TCT CCA GTT GTA CAA CTT CAT TCT AA - #T TTC ACT GCA GTT TGT          144                                                                       Pro Glu Ser Pro Val Val Gln Leu His Ser As - #n Phe Thr Ala Val Cys                    35         - #         40         - #         45                      - - GTG CTA AAG GAA AAA TGT ATG GAT TAT TTT CA - #T GTA AAT GCT AAT TAC          192                                                                       Val Leu Lys Glu Lys Cys Met Asp Tyr Phe Hi - #s Val Asn Ala Asn Tyr                50             - #     55             - #     60                          - - ATT GTC TGG AAA ACA AAC CAT TTT ACT ATT CC - #T AAG GAG CAA TAT ACT          240                                                                       Ile Val Trp Lys Thr Asn His Phe Thr Ile Pr - #o Lys Glu Gln Tyr Thr            65                 - # 70                 - # 75                 - # 80       - - ATC ATA AAC AGA ACA GCA TCC AGT GTC ACC TT - #T ACA GAT ATA GCT TCA          288                                                                       Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Ph - #e Thr Asp Ile Ala Ser                            85 - #                 90 - #                 95              - - TTA AAT ATT CAG CTC ACT TGC AAC ATT CTT AC - #A TTC GGA CAG CTT GAA          336                                                                       Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Th - #r Phe Gly Gln Leu Glu                       100      - #           105      - #           110                  - - CAG AAT GTT TAT GGA ATC ACA ATA ATT TCA GG - #C TTG CCT CCA GAA AAA          384                                                                       Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gl - #y Leu Pro Pro Glu Lys                   115          - #       120          - #       125                      - - CCT AAA AAT TTG AGT TGC ATT GTG AAC GAG GG - #G AAG AAA ATG AGG TGT          432                                                                       Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gl - #y Lys Lys Met Arg Cys               130              - #   135              - #   140                          - - GAG TGG GAT GGT GGA AGG GAA ACA CAC TTG GA - #G ACA AAC TTC ACT TTA          480                                                                       Glu Trp Asp Gly Gly Arg Glu Thr His Leu Gl - #u Thr Asn Phe Thr Leu           145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - AAA TCT GAA TGG GCA ACA CAC AAG TTT GCT GA - #T TGC AAA GCA AAA        CGT      528                                                                    Lys Ser Glu Trp Ala Thr His Lys Phe Ala As - #p Cys Lys Ala Lys Arg                          165  - #               170  - #               175              - - GAC ACC CCC ACC TCA TGC ACT GTT GAT TAT TC - #T ACT GTG TAT TTT GTC          576                                                                       Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Se - #r Thr Val Tyr Phe Val                       180      - #           185      - #           190                  - - AAC ATT GAA GTC TGG GTA GAA GCA GAG AAT GC - #C CTT GGG AAG GTT ACA          624                                                                       Asn Ile Glu Val Trp Val Glu Ala Glu Asn Al - #a Leu Gly Lys Val Thr                   195          - #       200          - #       205                      - - TCA GAT CAT ATC AAT TTT GAT CCT GTA TAT AA - #A GTG AAG CCC AAT CCG          672                                                                       Ser Asp His Ile Asn Phe Asp Pro Val Tyr Ly - #s Val Lys Pro Asn Pro               210              - #   215              - #   220                          - - CCA CAT AAT TTA TCA GTG ATC AAC TCA GAG GA - #A CTG TCT AGT ATC TTA          720                                                                       Pro His Asn Leu Ser Val Ile Asn Ser Glu Gl - #u Leu Ser Ser Ile Leu           225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - AAA TTG ACA TGG ACC AAC CCA AGT ATT AAG AG - #T GTT ATA ATA CTA        AAA      768                                                                    Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Se - #r Val Ile Ile Leu Lys                          245  - #               250  - #               255              - - TAT AAC ATT CAA TAT AGG ACC AAA GAT GCC TC - #A ACT TGG AGC CAG ATT          816                                                                       Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Se - #r Thr Trp Ser Gln Ile                       260      - #           265      - #           270                  - - CCT CCT GAA GAC ACA GCA TCC ACC CGA TCT TC - #A TTC ACT GTC CAA GAC          864                                                                       Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Se - #r Phe Thr Val Gln Asp                   275          - #       280          - #       285                      - - CTT AAA CCT TTT ACA GAA TAT GTG TTT AGG AT - #T CGC TGT ATG AAG GAA          912                                                                       Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Il - #e Arg Cys Met Lys Glu               290              - #   295              - #   300                          - - GAT GGT AAG GGA TAC TGG AGT GAC TGG AGT GA - #A GAA GCA AGT GGG ATC          960                                                                       Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Gl - #u Glu Ala Ser Gly Ile           305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - ACC TAT GAA GAT AGA CCA TCT AAA GCA CCA AG - #T TTC TGG TAT AAA        ATA     1008                                                                    Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Se - #r Phe Trp Tyr Lys Ile                          325  - #               330  - #               335              - - GAT CCA TCC CAT ACT CAA GGC TAC AGA ACT GT - #A CAA CTC GTG TGG AAG         1056                                                                       Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Va - #l Gln Leu Val Trp Lys                       340      - #           345      - #           350                  - - ACA TTG CCT CCT TTT GAA GCC AAT GGA AAA AT - #C TTG GAT TAT GAA GTG         1104                                                                       Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Il - #e Leu Asp Tyr Glu Val                   355          - #       360          - #       365                      - - ACT CTC ACA AGA TGG AAA TCA CAT TTA CAA AA - #T TAC ACA GTT AAT GCC         1152                                                                       Thr Leu Thr Arg Trp Lys Ser His Leu Gln As - #n Tyr Thr Val Asn Ala               370              - #   375              - #   380                          - - ACA AAA CTG ACA GTA AAT CTC ACA AAT GAT CG - #C TAT CTA GCA ACC CTA         1200                                                                       Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Ar - #g Tyr Leu Ala Thr Leu           385                 3 - #90                 3 - #95                 4 -      #00                                                                              - - ACA GTA AGA AAT CTT GTT GGC AAA TCA GAT GC - #A GCT GTT TTA ACT        ATC     1248                                                                    Thr Val Arg Asn Leu Val Gly Lys Ser Asp Al - #a Ala Val Leu Thr Ile                          405  - #               410  - #               415              - - CCT GCC TGT GAC TTT CAA GCT ACT CAC CCT GT - #A ATG GAT CTT AAA GCA         1296                                                                       Pro Ala Cys Asp Phe Gln Ala Thr His Pro Va - #l Met Asp Leu Lys Ala                       420      - #           425      - #           430                  - - TTC CCC AAA GAT AAC ATG CTT TGG GTG GAA TG - #G ACT ACT CCA AGG GAA         1344                                                                       Phe Pro Lys Asp Asn Met Leu Trp Val Glu Tr - #p Thr Thr Pro Arg Glu                   435          - #       440          - #       445                      - - TCT GTA AAG AAA TAT ATA CTT GAG TGG TGT GT - #G TTA TCA GAT AAA GCA         1392                                                                       Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Va - #l Leu Ser Asp Lys Ala               450              - #   455              - #   460                          - - CCC TGT ATC ACA GAC TGG CAA CAA GAA GAT GG - #T ACC GTG CAT CGC ACC         1440                                                                       Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gl - #y Thr Val His Arg Thr           465                 4 - #70                 4 - #75                 4 -      #80                                                                              - - TAT TTA AGA GGG AAC TTA GCA GAG AGC AAA TG - #C TAT TTG ATA ACA        GTT     1488                                                                    Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cy - #s Tyr Leu Ile Thr Val                          485  - #               490  - #               495              - - ACT CCA GTA TAT GCT GAT GGA CCA GGA AGC CC - #T GAA TCC ATA AAG GCA         1536                                                                       Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pr - #o Glu Ser Ile Lys Ala                       500      - #           505      - #           510                  - - TAC CTT AAA CAA GCT CCA CCT TCC AAA GGA CC - #T ACT GTT CGG ACA AAA         1584                                                                       Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pr - #o Thr Val Arg Thr Lys                   515          - #       520          - #       525                      - - AAA GTA GGG AAA AAC GAA GCT GTC TTA GAG TG - #G GAC CAA CTT CCT GTT         1632                                                                       Lys Val Gly Lys Asn Glu Ala Val Leu Glu Tr - #p Asp Gln Leu Pro Val               530              - #   535              - #   540                          - - GAT GTT CAG AAT GGA TTT ATC AGA AAT TAT AC - #T ATA TTT TAT AGA ACC         1680                                                                       Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Th - #r Ile Phe Tyr Arg Thr           545                 5 - #50                 5 - #55                 5 -      #60                                                                              - - ATC ATT GGA AAT GAA ACT GCT GTG AAT GTG GA - #T TCT TCC CAC ACA        GAA     1728                                                                    Ile Ile Gly Asn Glu Thr Ala Val Asn Val As - #p Ser Ser His Thr Glu                          565  - #               570  - #               575              - - TAT ACA TTG TCC TCT TTG ACT AGT GAC ACA TT - #G TAC ATG GTA CGA ATG         1776                                                                       Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Le - #u Tyr Met Val Arg Met                       580      - #           585      - #           590                  - - GCA GCA TAC ACA GAT GAA GGT GGG AAG GAT GG - #T CCA GAA TTC ACT TTT         1824                                                                       Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gl - #y Pro Glu Phe Thr Phe                   595          - #       600          - #       605                      - - ACT ACC CCA AAG TTT GAA TTA AAA AAC ACA TC - #T GGC CTA ATG TTC CAG         1872                                                                       Thr Thr Pro Lys Phe Glu Leu Lys Asn Thr Se - #r Gly Leu Met Phe Gln               610              - #   615              - #   620                          - - ATC CTT CAA AGA GTC ATA TTG CCC AGT GGT CA - #C CTC ACA CTC CTC CAA         1920                                                                       Ile Leu Gln Arg Val Ile Leu Pro Ser Gly Hi - #s Leu Thr Leu Leu Gln           625                 6 - #30                 6 - #35                 6 -      #40                                                                              - - GGC ACA ATT TTA ATT CAA AAG ATC AAA TGT AT - #T CAG ATG GCA ATT        TCA     1968                                                                    Gly Thr Ile Leu Ile Gln Lys Ile Lys Cys Il - #e Gln Met Ala Ile Ser                          645  - #               650  - #               655              - - CTG ATG TAA              - #                  - #                       - #       1977                                                                  Leu Met                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO:4:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 658 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                               - - Met Leu Thr Leu Gln Thr Trp Val Val Gln Al - #a Leu Phe Ile Phe        Leu                                                                               1               5 - #                 10 - #                 15             - - Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pr - #o Cys Gly Tyr Ile Ser                   20     - #             25     - #             30                  - - Pro Glu Ser Pro Val Val Gln Leu His Ser As - #n Phe Thr Ala Val Cys               35         - #         40         - #         45                      - - Val Leu Lys Glu Lys Cys Met Asp Tyr Phe Hi - #s Val Asn Ala Asn Tyr           50             - #     55             - #     60                          - - Ile Val Trp Lys Thr Asn His Phe Thr Ile Pr - #o Lys Glu Gln Tyr Thr       65                 - # 70                 - # 75                 - # 80       - - Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Ph - #e Thr Asp Ile Ala Ser                       85 - #                 90 - #                 95              - - Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Th - #r Phe Gly Gln Leu Glu                  100      - #           105      - #           110                  - - Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gl - #y Leu Pro Pro Glu Lys              115          - #       120          - #       125                      - - Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gl - #y Lys Lys Met Arg Cys          130              - #   135              - #   140                          - - Glu Trp Asp Gly Gly Arg Glu Thr His Leu Gl - #u Thr Asn Phe Thr Leu      145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - Lys Ser Glu Trp Ala Thr His Lys Phe Ala As - #p Cys Lys Ala Lys        Arg                                                                                             165  - #               170  - #               175             - - Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Se - #r Thr Val Tyr Phe Val                  180      - #           185      - #           190                  - - Asn Ile Glu Val Trp Val Glu Ala Glu Asn Al - #a Leu Gly Lys Val Thr              195          - #       200          - #       205                      - - Ser Asp His Ile Asn Phe Asp Pro Val Tyr Ly - #s Val Lys Pro Asn Pro          210              - #   215              - #   220                          - - Pro His Asn Leu Ser Val Ile Asn Ser Glu Gl - #u Leu Ser Ser Ile Leu      225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Se - #r Val Ile Ile Leu        Lys                                                                                             245  - #               250  - #               255             - - Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Se - #r Thr Trp Ser Gln Ile                  260      - #           265      - #           270                  - - Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Se - #r Phe Thr Val Gln Asp              275          - #       280          - #       285                      - - Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Il - #e Arg Cys Met Lys Glu          290              - #   295              - #   300                          - - Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Gl - #u Glu Ala Ser Gly Ile      305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Se - #r Phe Trp Tyr Lys        Ile                                                                                             325  - #               330  - #               335             - - Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Va - #l Gln Leu Val Trp Lys                  340      - #           345      - #           350                  - - Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Il - #e Leu Asp Tyr Glu Val              355          - #       360          - #       365                      - - Thr Leu Thr Arg Trp Lys Ser His Leu Gln As - #n Tyr Thr Val Asn Ala          370              - #   375              - #   380                          - - Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Ar - #g Tyr Leu Ala Thr Leu      385                 3 - #90                 3 - #95                 4 -      #00                                                                              - - Thr Val Arg Asn Leu Val Gly Lys Ser Asp Al - #a Ala Val Leu Thr        Ile                                                                                             405  - #               410  - #               415             - - Pro Ala Cys Asp Phe Gln Ala Thr His Pro Va - #l Met Asp Leu Lys Ala                  420      - #           425      - #           430                  - - Phe Pro Lys Asp Asn Met Leu Trp Val Glu Tr - #p Thr Thr Pro Arg Glu              435          - #       440          - #       445                      - - Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Va - #l Leu Ser Asp Lys Ala          450              - #   455              - #   460                          - - Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gl - #y Thr Val His Arg Thr      465                 4 - #70                 4 - #75                 4 -      #80                                                                              - - Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cy - #s Tyr Leu Ile Thr        Val                                                                                             485  - #               490  - #               495             - - Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pr - #o Glu Ser Ile Lys Ala                  500      - #           505      - #           510                  - - Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pr - #o Thr Val Arg Thr Lys              515          - #       520          - #       525                      - - Lys Val Gly Lys Asn Glu Ala Val Leu Glu Tr - #p Asp Gln Leu Pro Val          530              - #   535              - #   540                          - - Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Th - #r Ile Phe Tyr Arg Thr      545                 5 - #50                 5 - #55                 5 -      #60                                                                              - - Ile Ile Gly Asn Glu Thr Ala Val Asn Val As - #p Ser Ser His Thr        Glu                                                                                             565  - #               570  - #               575             - - Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Le - #u Tyr Met Val Arg Met                  580      - #           585      - #           590                  - - Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gl - #y Pro Glu Phe Thr Phe              595          - #       600          - #       605                      - - Thr Thr Pro Lys Phe Glu Leu Lys Asn Thr Se - #r Gly Leu Met Phe Gln          610              - #   615              - #   620                          - - Ile Leu Gln Arg Val Ile Leu Pro Ser Gly Hi - #s Leu Thr Leu Leu Gln      625                 6 - #30                 6 - #35                 6 -      #40                                                                              - - Gly Thr Ile Leu Ile Gln Lys Ile Lys Cys Il - #e Gln Met Ala Ile        Ser                                                                                             645  - #               650  - #               655             - - Leu Met                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:5:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 2754 base - #pairs                                                (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (ix) FEATURE:                                                                  (A) NAME/KEY: CDS                                                             (B) LOCATION: 1..2754                                                - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                               - - ATG TTG ACG TTG CAG ACT TGG GTA GTG CAA GC - #C TTG TTT ATT TTC CTC           48                                                                       Met Leu Thr Leu Gln Thr Trp Val Val Gln Al - #a Leu Phe Ile Phe Leu             1               5 - #                 10 - #                 15              - - ACC ACT GAA TCT ACA GGT GAA CTT CTA GAT CC - #A TGT GGT TAT ATC AGT           96                                                                       Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pr - #o Cys Gly Tyr Ile Ser                        20     - #             25     - #             30                  - - CCT GAA TCT CCA GTT GTA CAA CTT CAT TCT AA - #T TTC ACT GCA GTT TGT          144                                                                       Pro Glu Ser Pro Val Val Gln Leu His Ser As - #n Phe Thr Ala Val Cys                    35         - #         40         - #         45                      - - GTG CTA AAG GAA AAA TGT ATG GAT TAT TTT CA - #T GTA AAT GCT AAT TAC          192                                                                       Val Leu Lys Glu Lys Cys Met Asp Tyr Phe Hi - #s Val Asn Ala Asn Tyr                50             - #     55             - #     60                          - - ATT GTC TGG AAA ACA AAC CAT TTT ACT ATT CC - #T AAG GAG CAA TAT ACT          240                                                                       Ile Val Trp Lys Thr Asn His Phe Thr Ile Pr - #o Lys Glu Gln Tyr Thr            65                 - # 70                 - # 75                 - # 80       - - ATC ATA AAC AGA ACA GCA TCC AGT GTC ACC TT - #T ACA GAT ATA GCT TCA          288                                                                       Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Ph - #e Thr Asp Ile Ala Ser                            85 - #                 90 - #                 95              - - TTA AAT ATT CAG CTC ACT TGC AAC ATT CTT AC - #A TTC GGA CAG CTT GAA          336                                                                       Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Th - #r Phe Gly Gln Leu Glu                       100      - #           105      - #           110                  - - CAG AAT GTT TAT GGA ATC ACA ATA ATT TCA GG - #C TTG CCT CCA GAA AAA          384                                                                       Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gl - #y Leu Pro Pro Glu Lys                   115          - #       120          - #       125                      - - CCT AAA AAT TTG AGT TGC ATT GTG AAC GAG GG - #G AAG AAA ATG AGG TGT          432                                                                       Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gl - #y Lys Lys Met Arg Cys               130              - #   135              - #   140                          - - GAG TGG GAT GGT GGA AGG GAA ACA CAC TTG GA - #G ACA AAC TTC ACT TTA          480                                                                       Glu Trp Asp Gly Gly Arg Glu Thr His Leu Gl - #u Thr Asn Phe Thr Leu           145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - AAA TCT GAA TGG GCA ACA CAC AAG TTT GCT GA - #T TGC AAA GCA AAA        CGT      528                                                                    Lys Ser Glu Trp Ala Thr His Lys Phe Ala As - #p Cys Lys Ala Lys Arg                          165  - #               170  - #               175              - - GAC ACC CCC ACC TCA TGC ACT GTT GAT TAT TC - #T ACT GTG TAT TTT GTC          576                                                                       Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Se - #r Thr Val Tyr Phe Val                       180      - #           185      - #           190                  - - AAC ATT GAA GTC TGG GTA GAA GCA GAG AAT GC - #C CTT GGG AAG GTT ACA          624                                                                       Asn Ile Glu Val Trp Val Glu Ala Glu Asn Al - #a Leu Gly Lys Val Thr                   195          - #       200          - #       205                      - - TCA GAT CAT ATC AAT TTT GAT CCT GTA TAT AA - #A GTG AAG CCC AAT CCG          672                                                                       Ser Asp His Ile Asn Phe Asp Pro Val Tyr Ly - #s Val Lys Pro Asn Pro               210              - #   215              - #   220                          - - CCA CAT AAT TTA TCA GTG ATC AAC TCA GAG GA - #A CTG TCT AGT ATC TTA          720                                                                       Pro His Asn Leu Ser Val Ile Asn Ser Glu Gl - #u Leu Ser Ser Ile Leu           225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - AAA TTG ACA TGG ACC AAC CCA AGT ATT AAG AG - #T GTT ATA ATA CTA        AAA      768                                                                    Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Se - #r Val Ile Ile Leu Lys                          245  - #               250  - #               255              - - TAT AAC ATT CAA TAT AGG ACC AAA GAT GCC TC - #A ACT TGG AGC CAG ATT          816                                                                       Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Se - #r Thr Trp Ser Gln Ile                       260      - #           265      - #           270                  - - CCT CCT GAA GAC ACA GCA TCC ACC CGA TCT TC - #A TTC ACT GTC CAA GAC          864                                                                       Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Se - #r Phe Thr Val Gln Asp                   275          - #       280          - #       285                      - - CTT AAA CCT TTT ACA GAA TAT GTG TTT AGG AT - #T CGC TGT ATG AAG GAA          912                                                                       Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Il - #e Arg Cys Met Lys Glu               290              - #   295              - #   300                          - - GAT GGT AAG GGA TAC TGG AGT GAC TGG AGT GA - #A GAA GCA AGT GGG ATC          960                                                                       Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Gl - #u Glu Ala Ser Gly Ile           305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - ACC TAT GAA GAT AGA CCA TCT AAA GCA CCA AG - #T TTC TGG TAT AAA        ATA     1008                                                                    Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Se - #r Phe Trp Tyr Lys Ile                          325  - #               330  - #               335              - - GAT CCA TCC CAT ACT CAA GGC TAC AGA ACT GT - #A CAA CTC GTG TGG AAG         1056                                                                       Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Va - #l Gln Leu Val Trp Lys                       340      - #           345      - #           350                  - - ACA TTG CCT CCT TTT GAA GCC AAT GGA AAA AT - #C TTG GAT TAT GAA GTG         1104                                                                       Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Il - #e Leu Asp Tyr Glu Val                   355          - #       360          - #       365                      - - ACT CTC ACA AGA TGG AAA TCA CAT TTA CAA AA - #T TAC ACA GTT AAT GCC         1152                                                                       Thr Leu Thr Arg Trp Lys Ser His Leu Gln As - #n Tyr Thr Val Asn Ala               370              - #   375              - #   380                          - - ACA AAA CTG ACA GTA AAT CTC ACA AAT GAT CG - #C TAT CTA GCA ACC CTA         1200                                                                       Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Ar - #g Tyr Leu Ala Thr Leu           385                 3 - #90                 3 - #95                 4 -      #00                                                                              - - ACA GTA AGA AAT CTT GTT GGC AAA TCA GAT GC - #A GCT GTT TTA ACT        ATC     1248                                                                    Thr Val Arg Asn Leu Val Gly Lys Ser Asp Al - #a Ala Val Leu Thr Ile                          405  - #               410  - #               415              - - CCT GCC TGT GAC TTT CAA GCT ACT CAC CCT GT - #A ATG GAT CTT AAA GCA         1296                                                                       Pro Ala Cys Asp Phe Gln Ala Thr His Pro Va - #l Met Asp Leu Lys Ala                       420      - #           425      - #           430                  - - TTC CCC AAA GAT AAC ATG CTT TGG GTG GAA TG - #G ACT ACT CCA AGG GAA         1344                                                                       Phe Pro Lys Asp Asn Met Leu Trp Val Glu Tr - #p Thr Thr Pro Arg Glu                   435          - #       440          - #       445                      - - TCT GTA AAG AAA TAT ATA CTT GAG TGG TGT GT - #G TTA TCA GAT AAA GCA         1392                                                                       Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Va - #l Leu Ser Asp Lys Ala               450              - #   455              - #   460                          - - CCC TGT ATC ACA GAC TGG CAA CAA GAA GAT GG - #T ACC GTG CAT CGC ACC         1440                                                                       Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gl - #y Thr Val His Arg Thr           465                 4 - #70                 4 - #75                 4 -      #80                                                                              - - TAT TTA AGA GGG AAC TTA GCA GAG AGC AAA TG - #C TAT TTG ATA ACA        GTT     1488                                                                    Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cy - #s Tyr Leu Ile Thr Val                          485  - #               490  - #               495              - - ACT CCA GTA TAT GCT GAT GGA CCA GGA AGC CC - #T GAA TCC ATA AAG GCA         1536                                                                       Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pr - #o Glu Ser Ile Lys Ala                       500      - #           505      - #           510                  - - TAC CTT AAA CAA GCT CCA CCT TCC AAA GGA CC - #T ACT GGT CGG ACA AAA         1584                                                                       Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pr - #o Thr Gly Arg Thr Lys                   515          - #       520          - #       525                      - - AAA GTA GGG AAA AAC GAA GCT GTC TTA GAG TG - #G GAC CAA CTT CCT GTT         1632                                                                       Lys Val Gly Lys Asn Glu Ala Val Leu Glu Tr - #p Asp Gln Leu Pro Val               530              - #   535              - #   540                          - - GAT GTT CAG AAT GGA TTT ATC AGA AAT TAT AC - #T ATA TTT TAT AGA ACC         1680                                                                       Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Th - #r Ile Phe Tyr Arg Thr           545                 5 - #50                 5 - #55                 5 -      #60                                                                              - - ATC ATT GGA AAT GAA ACT GCT GTG AAT GTG GA - #T TCT TCC CAC ACA        GAA     1728                                                                    Ile Ile Gly Asn Glu Thr Ala Val Asn Val As - #p Ser Ser His Thr Glu                          565  - #               570  - #               575              - - TAT ACA TTG TCC TCT TTG ACT AGT GAC ACA TT - #G TAC ATG GTA CGA ATG         1776                                                                       Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Le - #u Tyr Met Val Arg Met                       580      - #           585      - #           590                  - - GCA GCA TAC ACA GAT GAA GGT GGG AAG GAT GG - #T CCA GAA TTC ACT TTT         1824                                                                       Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gl - #y Pro Glu Phe Thr Phe                   595          - #       600          - #       605                      - - ACT ACC CCA AAG TTT GCT CAA GGA GAA ATT GA - #A GCC ATA GTC GTG CCT         1872                                                                       Thr Thr Pro Lys Phe Ala Gln Gly Glu Ile Gl - #u Ala Ile Val Val Pro               610              - #   615              - #   620                          - - GTT TGC TTA GCA TTC CTA TTG ACA ACT CTT CT - #G GGA GTG CTG TTC TGC         1920                                                                       Val Cys Leu Ala Phe Leu Leu Thr Thr Leu Le - #u Gly Val Leu Phe Cys           625                 6 - #30                 6 - #35                 6 -      #40                                                                              - - TTT AAT AAG CGA GAC CTA ATT AAA AAA CAC AT - #C TGG CCT AAT GTT        CCA     1968                                                                    Phe Asn Lys Arg Asp Leu Ile Lys Lys His Il - #e Trp Pro Asn Val Pro                          645  - #               650  - #               655              - - GAT CCT TCA AAG AGT CAT ATT GCC CAG TGG TC - #A CCT CAC ACT CCT CCA         2016                                                                       Asp Pro Ser Lys Ser His Ile Ala Gln Trp Se - #r Pro His Thr Pro Pro                       660      - #           665      - #           670                  - - AGG CAC AAT TTT AAT TCA AAA GAT CAA ATG TA - #T TCA GAT GGC AAT TTC         2064                                                                       Arg His Asn Phe Asn Ser Lys Asp Gln Met Ty - #r Ser Asp Gly Asn Phe                   675          - #       680          - #       685                      - - ACT GAT GTA AGT GTT GTG GAA ATA GAA GCA AA - #T GAC AAA AAG CCT TTT         2112                                                                       Thr Asp Val Ser Val Val Glu Ile Glu Ala As - #n Asp Lys Lys Pro Phe               690              - #   695              - #   700                          - - CCA GAA GAT CTG AAA TCA TTG GAC CTG TTC AA - #A AAG GAA AAA ATT AAT         2160                                                                       Pro Glu Asp Leu Lys Ser Leu Asp Leu Phe Ly - #s Lys Glu Lys Ile Asn           705                 7 - #10                 7 - #15                 7 -      #20                                                                              - - ACT GAA GGA CAC AGC AGT GGT ATT GGG GGG TC - #T TCA TGC ATG TCA        TCT     2208                                                                    Thr Glu Gly His Ser Ser Gly Ile Gly Gly Se - #r Ser Cys Met Ser Ser                          725  - #               730  - #               735              - - TCT AGG CCA AGC ATT TCT AGC AGT GAT GAA AA - #T GAA TCT TCA CAA AAC         2256                                                                       Ser Arg Pro Ser Ile Ser Ser Ser Asp Glu As - #n Glu Ser Ser Gln Asn                       740      - #           745      - #           750                  - - ACT TCG AGC ACT GTC CAG TAT TCT ACC GTG GT - #A CAC AGT GGC TAC AGA         2304                                                                       Thr Ser Ser Thr Val Gln Tyr Ser Thr Val Va - #l His Ser Gly Tyr Arg                   755          - #       760          - #       765                      - - CAC CAA GTT CCG TCA GTC CAA GTC TTC TCA AG - #A TCC GAG TCT ACC CAG         2352                                                                       His Gln Val Pro Ser Val Gln Val Phe Ser Ar - #g Ser Glu Ser Thr Gln               770              - #   775              - #   780                          - - CCC TTG TTA GAT TCA GAG GAG CGG CCA GAA GA - #T CTA CAA TTA GTA GAT         2400                                                                       Pro Leu Leu Asp Ser Glu Glu Arg Pro Glu As - #p Leu Gln Leu Val Asp           785                 7 - #90                 7 - #95                 8 -      #00                                                                              - - CAT GTA GAT GGC GGT GAT GGT ATT TTG CCC AG - #G CAA CAG TAC TTC        AAA     2448                                                                    His Val Asp Gly Gly Asp Gly Ile Leu Pro Ar - #g Gln Gln Tyr Phe Lys                          805  - #               810  - #               815              - - CAG AAC TGC AGT CAG CAT GAA TCC AGT CCA GA - #T ATT TCA CAT TTT GAA         2496                                                                       Gln Asn Cys Ser Gln His Glu Ser Ser Pro As - #p Ile Ser His Phe Glu                       820      - #           825      - #           830                  - - AGG TCA AAG CAA GTT TCA TCA GTC AAT GAG GA - #A GAT TTT GTT AGA CTT         2544                                                                       Arg Ser Lys Gln Val Ser Ser Val Asn Glu Gl - #u Asp Phe Val Arg Leu                   835          - #       840          - #       845                      - - AAA CAG CAG ATT TCA GAT CAT ATT TCA CAA TC - #C TGT GGA TCT GGG CAA         2592                                                                       Lys Gln Gln Ile Ser Asp His Ile Ser Gln Se - #r Cys Gly Ser Gly Gln               850              - #   855              - #   860                          - - ATG AAA ATG TTT CAG GAA GTT TCT GCA GCA GA - #T GCT TTT GGT CCA GGT         2640                                                                       Met Lys Met Phe Gln Glu Val Ser Ala Ala As - #p Ala Phe Gly Pro Gly           865                 8 - #70                 8 - #75                 8 -      #80                                                                              - - ACT GAG GGA CAA GTA GAA AGA TTT GAA ACA GT - #T GGC ATG GAG GCT        GCG     2688                                                                    Thr Glu Gly Gln Val Glu Arg Phe Glu Thr Va - #l Gly Met Glu Ala Ala                          885  - #               890  - #               895              - - ACT GAT GAA GGC ATG CCT AAA AGT TAC TTA CC - #A CAG ACT GTA CGG CAA         2736                                                                       Thr Asp Glu Gly Met Pro Lys Ser Tyr Leu Pr - #o Gln Thr Val Arg Gln                       900      - #           905      - #           910                  - - GGC GGC TAC ATG CCT CAG         - #                  - #                      - #2754                                                                  Gly Gly Tyr Met Pro Gln                                                               915                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO:6:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 918 amino - #acids                                                (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                               - - Met Leu Thr Leu Gln Thr Trp Val Val Gln Al - #a Leu Phe Ile Phe Leu        1               5 - #                 10 - #                 15              - - Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pr - #o Cys Gly Tyr Ile Ser                   20     - #             25     - #             30                  - - Pro Glu Ser Pro Val Val Gln Leu His Ser As - #n Phe Thr Ala Val Cys               35         - #         40         - #         45                      - - Val Leu Lys Glu Lys Cys Met Asp Tyr Phe Hi - #s Val Asn Ala Asn Tyr           50             - #     55             - #     60                          - - Ile Val Trp Lys Thr Asn His Phe Thr Ile Pr - #o Lys Glu Gln Tyr Thr       65                 - # 70                 - # 75                 - # 80       - - Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Ph - #e Thr Asp Ile Ala Ser                       85 - #                 90 - #                 95              - - Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Th - #r Phe Gly Gln Leu Glu                  100      - #           105      - #           110                  - - Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gl - #y Leu Pro Pro Glu Lys              115          - #       120          - #       125                      - - Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gl - #y Lys Lys Met Arg Cys          130              - #   135              - #   140                          - - Glu Trp Asp Gly Gly Arg Glu Thr His Leu Gl - #u Thr Asn Phe Thr Leu      145                 1 - #50                 1 - #55                 1 -      #60                                                                              - - Lys Ser Glu Trp Ala Thr His Lys Phe Ala As - #p Cys Lys Ala Lys        Arg                                                                                             165  - #               170  - #               175             - - Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Se - #r Thr Val Tyr Phe Val                  180      - #           185      - #           190                  - - Asn Ile Glu Val Trp Val Glu Ala Glu Asn Al - #a Leu Gly Lys Val Thr              195          - #       200          - #       205                      - - Ser Asp His Ile Asn Phe Asp Pro Val Tyr Ly - #s Val Lys Pro Asn Pro          210              - #   215              - #   220                          - - Pro His Asn Leu Ser Val Ile Asn Ser Glu Gl - #u Leu Ser Ser Ile Leu      225                 2 - #30                 2 - #35                 2 -      #40                                                                              - - Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Se - #r Val Ile Ile Leu        Lys                                                                                             245  - #               250  - #               255             - - Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Se - #r Thr Trp Ser Gln Ile                  260      - #           265      - #           270                  - - Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Se - #r Phe Thr Val Gln Asp              275          - #       280          - #       285                      - - Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Il - #e Arg Cys Met Lys Glu          290              - #   295              - #   300                          - - Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Gl - #u Glu Ala Ser Gly Ile      305                 3 - #10                 3 - #15                 3 -      #20                                                                              - - Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Se - #r Phe Trp Tyr Lys        Ile                                                                                             325  - #               330  - #               335             - - Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Va - #l Gln Leu Val Trp Lys                  340      - #           345      - #           350                  - - Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Il - #e Leu Asp Tyr Glu Val              355          - #       360          - #       365                      - - Thr Leu Thr Arg Trp Lys Ser His Leu Gln As - #n Tyr Thr Val Asn Ala          370              - #   375              - #   380                          - - Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Ar - #g Tyr Leu Ala Thr Leu      385                 3 - #90                 3 - #95                 4 -      #00                                                                              - - Thr Val Arg Asn Leu Val Gly Lys Ser Asp Al - #a Ala Val Leu Thr        Ile                                                                                             405  - #               410  - #               415             - - Pro Ala Cys Asp Phe Gln Ala Thr His Pro Va - #l Met Asp Leu Lys Ala                  420      - #           425      - #           430                  - - Phe Pro Lys Asp Asn Met Leu Trp Val Glu Tr - #p Thr Thr Pro Arg Glu              435          - #       440          - #       445                      - - Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Va - #l Leu Ser Asp Lys Ala          450              - #   455              - #   460                          - - Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gl - #y Thr Val His Arg Thr      465                 4 - #70                 4 - #75                 4 -      #80                                                                              - - Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cy - #s Tyr Leu Ile Thr        Val                                                                                             485  - #               490  - #               495             - - Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pr - #o Glu Ser Ile Lys Ala                  500      - #           505      - #           510                  - - Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pr - #o Thr Gly Arg Thr Lys              515          - #       520          - #       525                      - - Lys Val Gly Lys Asn Glu Ala Val Leu Glu Tr - #p Asp Gln Leu Pro Val          530              - #   535              - #   540                          - - Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Th - #r Ile Phe Tyr Arg Thr      545                 5 - #50                 5 - #55                 5 -      #60                                                                              - - Ile Ile Gly Asn Glu Thr Ala Val Asn Val As - #p Ser Ser His Thr        Glu                                                                                             565  - #               570  - #               575             - - Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Le - #u Tyr Met Val Arg Met                  580      - #           585      - #           590                  - - Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gl - #y Pro Glu Phe Thr Phe              595          - #       600          - #       605                      - - Thr Thr Pro Lys Phe Ala Gln Gly Glu Ile Gl - #u Ala Ile Val Val Pro          610              - #   615              - #   620                          - - Val Cys Leu Ala Phe Leu Leu Thr Thr Leu Le - #u Gly Val Leu Phe Cys      625                 6 - #30                 6 - #35                 6 -      #40                                                                              - - Phe Asn Lys Arg Asp Leu Ile Lys Lys His Il - #e Trp Pro Asn Val        Pro                                                                                             645  - #               650  - #               655             - - Asp Pro Ser Lys Ser His Ile Ala Gln Trp Se - #r Pro His Thr Pro Pro                  660      - #           665      - #           670                  - - Arg His Asn Phe Asn Ser Lys Asp Gln Met Ty - #r Ser Asp Gly Asn Phe              675          - #       680          - #       685                      - - Thr Asp Val Ser Val Val Glu Ile Glu Ala As - #n Asp Lys Lys Pro Phe          690              - #   695              - #   700                          - - Pro Glu Asp Leu Lys Ser Leu Asp Leu Phe Ly - #s Lys Glu Lys Ile Asn      705                 7 - #10                 7 - #15                 7 -      #20                                                                              - - Thr Glu Gly His Ser Ser Gly Ile Gly Gly Se - #r Ser Cys Met Ser        Ser                                                                                             725  - #               730  - #               735             - - Ser Arg Pro Ser Ile Ser Ser Ser Asp Glu As - #n Glu Ser Ser Gln Asn                  740      - #           745      - #           750                  - - Thr Ser Ser Thr Val Gln Tyr Ser Thr Val Va - #l His Ser Gly Tyr Arg              755          - #       760          - #       765                      - - His Gln Val Pro Ser Val Gln Val Phe Ser Ar - #g Ser Glu Ser Thr Gln          770              - #   775              - #   780                          - - Pro Leu Leu Asp Ser Glu Glu Arg Pro Glu As - #p Leu Gln Leu Val Asp      785                 7 - #90                 7 - #95                 8 -      #00                                                                              - - His Val Asp Gly Gly Asp Gly Ile Leu Pro Ar - #g Gln Gln Tyr Phe        Lys                                                                                             805  - #               810  - #               815             - - Gln Asn Cys Ser Gln His Glu Ser Ser Pro As - #p Ile Ser His Phe Glu                  820      - #           825      - #           830                  - - Arg Ser Lys Gln Val Ser Ser Val Asn Glu Gl - #u Asp Phe Val Arg Leu              835          - #       840          - #       845                      - - Lys Gln Gln Ile Ser Asp His Ile Ser Gln Se - #r Cys Gly Ser Gly Gln          850              - #   855              - #   860                          - - Met Lys Met Phe Gln Glu Val Ser Ala Ala As - #p Ala Phe Gly Pro Gly      865                 8 - #70                 8 - #75                 8 -      #80                                                                              - - Thr Glu Gly Gln Val Glu Arg Phe Glu Thr Va - #l Gly Met Glu Ala        Ala                                                                                             885  - #               890  - #               895             - - Thr Asp Glu Gly Met Pro Lys Ser Tyr Leu Pr - #o Gln Thr Val Arg Gln                  900      - #           905      - #           910                  - - Gly Gly Tyr Met Pro Gln                                                          915                                                                    - -  - - (2) INFORMATION FOR SEQ ID NO:7:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                               - - CCGCAGGTCG AGACAGC             - #                  - #                      - #   17                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:8:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                               - - CAAACACCTT CTCGCGAA             - #                  - #                      - #  18                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:9:                                     - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                               - - CTTCAGGGAG AGCGCGTGC             - #                  - #                      - # 19                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:10:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                              - - TCATCAGGAC CCAGCTGTGC            - #                  - #                      - # 20                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:11:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 21 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                              - - TTGACTAGTG ACACATTGTA C           - #                  - #                      - #21                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:12:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                              - - TGAAACTTGC TTTGACCTTT            - #                  - #                      - # 20                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:13:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                              - - GGTACGAATG GCAGCATACA            - #                  - #                      - # 20                                                                   - -  - - (2) INFORMATION FOR SEQ ID NO:14:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: both                                                        (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: cDNA                                              - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                              - - CTGGACTGGA TTCATGCTGA            - #                  - #                      - # 20                                                                 __________________________________________________________________________

We claim:
 1. An isolated and substantially purified DNA coding for aprotein having the amino acid sequence of SEQ ID NO:4.
 2. The DNA asclaimed in claim 1 which hybridises under stringent conditions ofbetween 35° C. to 65° C. and a salt concentration of about 0.9 M to theDNA sequence of SEQ ID NO:3.
 3. A recombiant DNA comprising DNA asdefined in claim 1 or claim 2.